RU2495042C2 - Nalmefene prodrugs - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to ester prodrug forms of nalmefene of formula (I)

wherein R₁ means C_6-16alkyl or C_8-12alkylamino; or a pharmaceutically acceptable acid additive salt thereof. Also the invention claims the pharmaceutical compositions possessing action of an opioid receptor agonist containing a pharmaceutically acceptable salt and a therapeutically acceptable amount of the compound of formula (I).

EFFECT: invention describes the chemical methods for preparing the above compounds and using them in treating substance abuse disorders, such as abuse of alcohol and alcohol dependence, and pulse control disorders, such as compulsive gambling and shopping addiction.

14 cl, 5 ex, 1 tbl, 1 dwg

Description

The present invention relates to nalmefene ester prodrugs of the formula (I), to pharmaceutical compositions containing these compounds, to chemical methods for preparing such compounds and to their use for treating substance abuse disorders such as alcoholism and alcohol dependence, and disorders such like control over motives, pathological gambling and shopping.

Nalmefen is an opioid receptor antagonist that has been available for several years as an injectable Revex®, used to reverse the effects of opioids and in cases of opioid overdose. Nalmefen is also described in the literature as a medication for the treatment of substance abuse disorders such as alcohol dependence and impulse control disorders such as abnormal gambling and shopping. According to the IUPAC system, it has the following name: 17-cyclopropylmethyl-4,5α-epoxy-6-methylene morphinan-3,14-diol and is described by the structure below:

In Arch. Gen. Psychiatry, 56, 719-724 (1999) describes a double-blind, placebo-controlled study of alcohol dependence, where volunteers took oral doses of 20 or 80 mg of nalmefene daily for 12 weeks to evaluate the safety and effectiveness of this drug.

The Alcoholism publication: Clinical and Experimental Research, 31, 1179-1187 (2007), describes a multicenter, randomized, double-blind study of neglected alcoholics who was advised to take 10 to 40 mg of nalmefene orally when they needed alcohol. The study showed that nalmefen appears to be an effective and safe drug to reduce the need for alcohol in neglected alcoholics.

EP-0250796 describes prodrugs based on an aliphatic, aromatic, carbonate, carbamate and sulfonate ester of a large number of 3-hydroxymorphinans that do not have a bitter taste and, therefore, are suitable for use in an oral regimen such as buccal, nasal or sublingual introduction.

WO-03/070191 describes a tamper-resistant transdermal delivery device used in the treatment or prevention of pain, including an opioid. The described delivery device also contains an acylopioid antagonist, which is released when the toxicoman shakes the device in order to remove the opioid from the delivery device. Thus, the opioid antagonist dulls or suppresses the euphoric effects of the opioid.

Unfortunately, commercially used nalmefene preparations create therapeutically effective plasma levels only for a limited period of time. Long-acting standard forms of nalmefene could be useful for therapeutic purposes and facilitate patient compliance with the prescribed treatment regimen, which is very important in the treatment of substance abuse disorders and impulsive control disorders.

The authors found that prodrug forms of nalmefene of formula (I) maintain therapeutically relevant plasma levels of nalmefene for a long period of time. When the compounds of formula (I) are administered intramuscularly, they can ensure the maintenance of therapeutically relevant plasma levels of nalmefene for a period of time from several weeks to several months. And when the compounds of formula (I) are administered orally, they can maintain therapeutically relevant plasma levels of nalmefene for several days.

The present invention relates to a compound of formula (I)

including any stereochemically isomeric form, where

R ¹ is C _6-16 alkyl or C _8-12 alkylamino;

or a pharmaceutically acceptable acid addition salt or solvate thereof.

In the context of the present description, the following definitions apply:

C _8-12 alkyl refers to straight and branched saturated hydrocarbon radicals containing from 8 to 12 carbon atoms, such as, for example, octyl, nonyl, decyl, undecyl, dodecyl and the like; -C _6-16 alkyl refers to straight and branched saturated hydrocarbon radicals containing from 6 to 16 carbon atoms, such as, for example, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl, and t .P.;

-C _13-16 alkyl refers to straight and branched saturated hydrocarbon radicals containing from 13 to 16 carbon atoms, such as, for example, tridecyl, tetradecyl, pentadecyl and hexadecyl and the like.

The term "stereochemically isomeric forms" in the context of the present description refers to all possible isomeric forms that may exist in the compounds of formula (I). Unless otherwise specified or specifically indicated otherwise, the chemical name of the compounds refers to a mixture of all possible stereochemically isomeric forms, where these mixtures contain all diastereomers and enantiomers of the basic molecular structure. Moreover, stereogenic centers may have an R- or S-configuration. The stereochemically isomeric forms of the compounds of formula (I) are very definitely within the scope of the present invention.

The absolute stereochemical configuration of the compounds of formula (I) and the intermediates used in their manufacture can be easily determined by those skilled in the art using known methods, such as, for example, x-ray diffraction.

The above pharmaceutically acceptable acid addition salts include, in the context of the present description, therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are capable of forming. These pharmaceutically acceptable acid addition salts can be prepared by treating the base form of the compound with a suitable acid. Suitable acids for this include, for example, inorganic acids, such as hydrohalic acids, for example, hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and similar acids; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic(those. ethanedioic acid), malonic, succinic(those. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclamic, salicylic, para-aminosalicylic, pamoic and other acids.

Conversely, these salt forms when treated with an appropriate base can be converted into the free base form.

The compounds of formula (I) can exist in both unsolvated and solvated forms. The term “solvate” is used herein to mean a molecular association comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. The term "hydrate" is used in the text of the present description, when the specified solvent is a water.

A prodrug is a pharmacological substance (drug) that is administered in an inactive (or much less active) form. Once administered, the prodrug is metabolized in vivo to its active parent dosage form. The use of prodrugs is often useful, because in some situations they are easier to enter into the body than the original drug. They can, for example, demonstrate bioavailability when administered orally, whereas the parent product does not have this ability. The prodrug may also have increased solubility in the composition of the pharmaceutical compositions in comparison with the original drug or may have improved taste or it is more convenient to introduce into the composition.

The present invention, in one embodiment, relates to compounds of formula (I), wherein R ¹ is C _13-16 alkyl or C _8-12 alkylamino.

In another embodiment, the present invention relates to those compounds of formula (I) where one or more of the following restrictions apply:

a) R ¹ is C ₇ alkyl, C ₉ alkyl, C ₁₁ alkyl or C ₁₅ alkyl; or

b) R ¹ is n-heptyl, n-nonyl, n-undecyl or n-pentadecyl; or

c) R ¹ is C ₁₀ alkylamino; or

d) R ¹ is n-decylamino.

Compounds of formula (Ia), defined as compounds of formula (I), where R ¹ is C _6-16 alkyl, can be prepared by known esterification methods by reacting nalmefene (II) with an acyl halide of formula (III) in the presence of a base, with selection acid formed during the reaction. The substituent R ¹ in the acyl halide of formula (III) is defined as C _6-16 alkyl.

Compounds of formula (Ib), defined as compounds of formula (I), wherein R ¹ is C _8-12 alkylamino, can be prepared by reacting nalmefene (II) with an isocyanate of formula (IV).

The compounds of the present invention demonstrate the benefits of being a long-acting opioid receptor antagonist that are useful for treating substance abuse disorders such as alcoholism and alcohol dependence and impulse control disorders such as pathological gambling addiction and shopping. This ability can be confirmed, for example, by measuring the plasma content of these compounds after intramuscular administration to dogs, as described in Example C.1.

It has also been shown that when the prodrug of the compound of formula (I) is orally administered, the plasma content of nalmefene is determined for more than 8 days after the administration of the prodrug of the compound of formula (I), in comparison with the situation where the oral administration of nalmefene per se led to only hours of such identification.

In this regard, the compounds of the present invention make it possible to administer at relatively long time intervals, such as several days, several weeks, up to several months, while the actual time of administration depends on the physical nature of the compound used, the method of administration, the composition of the pharmaceutical dosage form the drug and the condition of the subject to be treated. Accordingly, the compounds of the present invention allow for more effective therapy: the sustained release of nalmefene facilitates the maintenance of a stable plasma concentration in the presence of a non-toxic therapeutically effective level, and the route of administration helps the subject comply with the prescribed treatment regimen. Accordingly, the compounds of the present invention can be used as a sustained release drug or as a sustained release drug.

An expression referring to “therapeutically relevant” or “therapeutically effective” plasma concentrations of nalmefene means that the plasma concentration of nalmefene (free nalmefene that has been released from the prodrug compounds of formula (I) of the present invention) should be above about 0.1 ng / ml

In this regard, the compounds of formula (I) of the present invention or their pharmaceutically acceptable acid addition salt or solvate can be used as a medicine, in particular, can be used as a medicine used to treat substance abuse disorders, such as alcohol addiction and alcoholism, and impulse control disorders such as pathological gambling and shopping addiction. In addition, the compounds of formula (I) of the present invention can be used as a medicine used to reduce the need for alcohol and its use in alcohol-dependent patients, as well as to reduce alcohol intake in dependent patients.

The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of substance abuse disorders such as alcohol addiction and alcoholism and impulse control disorders such as abnormal gambling and shopping.

In addition, the present invention relates to a method for treating substance abuse disorders or impulse control disorders in a mammalian subject, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof . Substance abuse disorders include alcohol dependence and alcoholism. Impulse control disorders include a pathological addiction to gambling and shopping.

The terms “treatment” and “therapy” in the context of the present description mean therapeutic, palliative and prophylactic treatment options that include reversing, alleviating, inhibiting the progression or preventing the development of the disease, disorder or condition to which the term refers, or one or more symptoms of such diseases, disorders or conditions.

Additionally, the present invention relates to pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

For the purpose of preparing the pharmaceutical compositions of the present invention, an effective amount of a particular compound in the form of a free base or an acid addition salt as an active ingredient is combined with thorough mixing with at least one pharmaceutically acceptable carrier, wherein said carrier can be presented in many different forms, depending on the form of the drug desired for the administration of the drug. Said pharmaceutical compositions are in unit dosage form, preferably suitable for oral administration, rectal administration, transdermal administration or for parenteral administration by injection.

For example, in the manufacture of compositions in the form of oral dosage forms, any standard liquid pharmaceutical carriers may be used, such as, for example, water, glycols, oils, alcohols, etc., in the case of the manufacture of liquid oral preparations, such as suspensions, syrups elixirs and solutions; or solid pharmaceutical carriers, such as starches, sugars, kaolin, lubricants, binders, decomposition aids, and the like, in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most convenient oral dosage unit form, in which case, obviously, solid pharmaceutical carriers are used. In the case of parenteral injectable compositions, the pharmaceutical carrier used may mainly include sterile water, although other ingredients may be included in the composition to increase the solubility of the active ingredient. Injectable solutions can be prepared, for example, using a pharmaceutical carrier that includes saline, glucose, or a mixture thereof. Injectable suspensions may also be prepared using appropriate liquid carriers, suspending agents, and the like. In compositions suitable for transdermal administration, said pharmaceutical carrier may optionally include a penetration enhancing agent and / or a suitable wetting agent, optionally in combination with small proportions of suitable additives that do not have a pronounced adverse effect on the skin. Such additives can be selected in order to make it more convenient to apply the active ingredient to the skin and / or to facilitate the preparation of the desired compositions. These topical compositions may be administered in various ways, such as a transdermal patch, spot-on patch, or ointment. Additive salts of the compounds of formula (I), due to their increased water solubility relative to the corresponding base form, are more suitable for the manufacture of aqueous compositions.

This is particularly preferable in the manufacturing process of the pharmaceutical compositions of the present invention in the form of a unit dosage form, due to the ease of administration and uniformity of the form obtained. The term “unit dosage form” as used herein refers to physically discrete units suitable as unit dosages, where each unit contains a predetermined amount of the active ingredient, calculated so that this amount creates the desired therapeutic effect in combination with the desired pharmaceutical carrier. Examples of such unit dosage forms include tablets (including notched or coated tablets), capsules, pills, powder sachets, cachets, injectable solutions or suspensions, dosage units appropriate for a teaspoon top, a tablespoon top and the like, as well as certain combination variants thereof.

For oral administration, the pharmaceutical compositions of the present invention can be presented in the form of solid dosage forms, for example tablets (both swallowed and chewable tablets), capsules or gelatine capsules prepared by conventional methods in combination with pharmaceutically acceptable excipients and carriers, such as binders (e.g. pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.), fillers (e.g. lactose, microcrystal cellulose, calcium phosphate, etc.), lubricants (e.g. magnesium stearate, talc, silicon dioxide, etc.), decomposition aids (e.g. potato starch, sodium starch glycolate, etc.) wetting agents (e.g. sodium lauryl sulfate) and the like Such tablets may also contain a coating applied by methods known in the art.

Liquid preparations for oral administration can be presented in the form of, for example, solutions, syrups or suspensions, or they can be prepared as a dry product, which is subsequently mixed with water and / or another suitable liquid carrier before use. Such liquid preparations can be prepared by standard methods, optionally using other pharmaceutically acceptable additives, such as suspending agents (e.g. sorbitol syrup, methyl cellulose, hydroxypropyl methyl cellulose or hydrogenated edible fats), emulsifiers (e.g. lecithin or gum arabic), non-aqueous vehicles (e.g. , almond oil, oil esters or ethyl alcohol), sweeteners, flavors, flavor enhancers and preservatives (e.g. methyl or propyl para-gi droxibenzoate or sorbic acid).

The pharmaceutically acceptable sweeteners used in the pharmaceutical compositions of the present invention preferably include at least one intense flavoring sweetener such as aspartame, potassium acesulfame, sodium cyclamate, alitam, hydroxychalonic sweetener, moneline, stevioside sucralose (4.1 ' 6'-trichloro-4,1 ', 6'-trideoxyhalactosaccharose) or preferably saccharin, sodium or calcium saccharin, and optionally at least one bulky sweetener such as sorbitol, mannitol, fructose, sucrose, maltose , Isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense flavor sweeteners are traditionally used in low concentrations. So, for example, in the case of sodium saccharin, this concentration may vary from about 0.04% to 0.1% (weight / volume) of the finished composition. The bulk sweetener can be used effectively at higher concentrations and vary from about 10% to about 35%, preferably from about 10% to about 15% (weight / volume).

Pharmaceutically acceptable flavors that can mask bitter tasting ingredients in low dose formulations preferably include fruit flavors, such as flavors based on cherries, raspberries, black currants or strawberries. The combination of two flavors can lead to very good results. Higher dose formulations may require stronger pharmaceutically acceptable flavors, such as caramel, chocolate, refreshing mint, fantasy compositions, and the like. Each flavoring substance may be present in the finished composition in a concentration ranging from about 0.05% to 1% (weight / volume). In this case, combinations of these stronger flavoring substances are successfully used. Preferably, flavors are used that do not undergo any change or do not lose their taste and / or color under the conditions of this composition.

The compounds of formula (I) can be prepared to provide a composition for parenteral administration by injection, usually intravenous, intramuscular or subcutaneous injection, for example, bolus injection or continuous intravenous infusion. Compositions for injection can be presented in unit dosage form, for example, can be in the form of ampoules or multi-dose containers, including a preservative added thereto. They may take the form of suspensions, solutions or emulsions in oil or aqueous vehicles and may contain agents included in the manufacture of the compositions, such as agents that support the maintenance of isotonic properties, suspending agents, stabilizing agents and / or dispersion aids. Alternatively, the active ingredient may be present in powder form, which is subsequently mixed with a suitable carrier, for example sterile, pyrogen-free water, before use. Compositions for intramuscular or subcutaneous administration are of particular interest. Such pharmaceutical compositions should not cause severe tissue irritation, or they should not cause tissue irritation or inflammation at the injection site. Suitable solvents include, for example, sesame oil or migliol.

The compounds of formula (I) can also be formulated as rectal compositions, such as suppositories or retention enemas, which, for example, contain standard suppository bases, such as cocoa butter and / or other glycerides.

experimental part

Example B.1

Palmitoyl chloride (16.1 ml, 53.2 mmol) was added dropwise over 30 minutes at ambient temperature to a stirred mixture of nalmefene hydrochloride (20.0 g, 1.0 equivalent), toluene (400 ml, 20 ml / g) and triethylamine (16.3 ml, 2.2 equivalents) in an inert atmosphere. Stirring at ambient temperature is continued for 16 hours. After that, the reaction mixture was washed with water (400 ml, 20 ml / g). After phase separation, the organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. Yield: 30.8 g (95%).

NMR:

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.08-0.16 (m, 2H), 0.43-0.53 (m, 2H), 0.81-0.89 (m, 4H), 1.14-1.42 (m, 26H ), 1.53 (dt, J = 12.78, 3.65, 3.46 Hz, 1H), 1.59-1.67 (m, J = 7.55, 7.55, 7.55, 7.55 Hz, 2H), 1.96 (td, J = 12.02, 3.65 Hz, 1H), 2.07 (dt, J = 13.66, 3.08, 2.90 Hz, 1H ), 2.24 (td, J = 12.53, 4.91 Hz, 1H), 2.35 (t, J = 6.04 Hz, 2H), 2.43-2.49 (m, 1H) 2.54 (t, J = 7.43 Hz, 2H), 2.53-2.61 (m, 1H) 2.62-2.68 (m, 1H), 3.03 (dd, J = 12.09, 6.55 Hz, 2H), 4.80 (d, J = 1.76 Hz, 1H), 4.91 (br s, 1H), 4.96 (s, 1H), 5, 05 (d, J = 1.26 Hz, 1H), 6.66 (d, J = 8.06 Hz, 1H), 6.77 (d, J = 8.31 Hz, 1H).

LC-MS

HR-MS (ES ⁺ ): Calculated for C ₃₇ H ₅₆ NO ₄ ⁺ : 578.4209. Found: 578.4199.

Elemental analysis

Analytically calculated for C ₃₇ H ₅₅ NO ₄ : C: 76.91; H: 9.59; N: 2.42. Found: C: 77.01; H: 9.96; N: 1.89.

Example B.2

Suspension of nalmefene hydrochloride (20.0 g, 53.2 mmol), toluene (400 ml, 20 ml / g), triethylamine (8.9 ml, 1.2 equivalents) and decylisocyanate (13.3 ml, 1.2 equivalents ) refluxed for 16 hours. Three more portions of decylisocyanate (2.2 ml, 0.2 equivalents; 2.2 ml, 0.2 equivalents and 4.4 ml, 0.4 equivalents, respectively) are added over the next 24 hours at reflux temperature. After the reaction mixture was cooled to ambient temperature, the mixture was washed with water (400 ml, 20 ml / g). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica 60–25-40 μg, 100% ethyl acetate) to obtain 17.4 g (63%) of compound (2).

NMR:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.06-0.17 (m, 2H), 0.41-0.53 (m, 2H), 0.78-0.91 (m, 4H), 1.22-1.31 (m, 16H) ), 1.40-1.48 (m, 2H), 1.52 (dt, J = 12.78, 3.56 Hz, 1H), 1.97 (td, J = 11.96, 3.53 Hz, 1H), 2.06 (dt, J = 13.60, 3.53 Hz, 1H), 2.23 (td, J = 12.46, 5.04 Hz, 1H), 2.35 (dd , J = 6.29, 3.78 Hz, 2H), 2.43-2.49 (m, 1H), 2.56 (dd, J = 18.88, 5.79 Hz, 1H), 2, 65 (dd, J = 11.71, 4.15 Hz, 1H), 2.97-3.08 (m, 4H), 4.79 (d, J = 1.51 Hz, 1H), 4.90 (s, 1H), 4.94 (s, 1H), 5.10 (d, J = 1.01 Hz, 1H), 6.62 (d, J = 8.06 Hz, 1H), 6.75 (d, J = 8.31 Hz, 1H); 7.63 (t, J = 5.67 Hz, 1H).

LC-MS:

HR-MS (ES ⁺ ): Calculated for C ₃₂ H ₄₇ N ₂ O ₄ ⁺ : 523.3536. Found: 523.3517.

Elemental analysis:

Analytically calculated for C ₃₂ H ₄₆ N ₂ O ₄ : C: 73.53; H: 8.87; N: 5.36. Found: C: 74.73; H: 9.45; N: 5.58.

Example B.3

Octanoyl chloride (2.27 ml, 13.3 mmol) was added dropwise over 30 minutes at ambient temperature to a mixed mixture of nalmefene hydrochloride (5 g, 1.0 equivalent), toluene (100 ml, 20 ml / g) and triethylamine (4.08 ml, 2.2 equivalents) in an inert atmosphere. Stirring at ambient temperature is continued for 16 hours. An additional 0.15 ml (0.07 equivalent) of octanoyl chloride was added. The solution was stirred for 4 hours at ambient temperature until the conversion process was completed. Then the reaction mixture was washed with water (400 ml, 20 ml / g). After phase separation, the organic layer was dried over magnesium sulfate and the filtrate was concentrated under reduced pressure to obtain 5.98 g (96%) of compound (3).

NMR:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.02-0.18 (m, 2H), 0.38-0.55 (m, 2H), 0.76-0.94 (m, 4H), 1.18-1.41 (m, 10H ), 1.53 (dt, J = 12.78, 3.30 Hz, 1H), 1.58-1.70 (m, 2H), 1.96 (td, J = 12.09, 3.78 Hz, 1H), 2.07 (td, J = 13.72, 3.15, 3.02 Hz, 1H), 2.24 (td, J = 12.59, 5.04 Hz, 1H), 2 , 31-2.40 (m, 2H), 2.45-2.50 (m, 1H), 2.54 (t, 2H), 2.53-2.61 (m, 1H), 2.65 (dd, J = 11.83, 4.28 Hz, 1H), 3.03 (dd, J = 12.09, 6.55 Hz, 2H), 4.80 (d, J = 1.76 Hz, 1H), 5.03 (br s, 1H), 4.96 (s, 1H), 5.05 (d, J = 1.26 Hz, 1H), 6.66 (d, J = 8.31 Hz, 1H), 6.76 (d, J = 8.06 Hz, 1H).

LC-MS: HRMS (ES +): Calculated for C ₂₉ H ₃₉ NO ₄ ⁺ : 466.2957. Found: 466.2967.

Example B.4

Decanoyl chloride (2.77 ml, 13.3 mmol) was added dropwise over 30 minutes at ambient temperature to a mixed mixture of nalmefene hydrochloride (5 g, 1.0 equivalent), toluene (100 ml, 20 ml / g) and triethylamine (4.08 ml, 2.2 equivalents) in an inert atmosphere. Stirring at ambient temperature is continued for 16 hours. Next, the reaction mixture was washed with water (400 ml, 20 ml / g). After phase separation, the organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 6.31 g (96%) of compound (4).

NMR:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.09-0.15 (m, 2H), 0.43-0.52 (m, 2H), 0.82-0.89 (m, 4H), 1.15-1.42 (m, 14H ), 1.53 (dt, J = 12.84, 3.40 Hz, 1H), 1.63 (q, J = 7.30 Hz, 2H), 1.96 (td, J = 12.09 , 3.78 Hz, 1H), 2.07 (dt, J = 13.60, 3.27 Hz, 1H), 2.24 (td, J = 12.53, 5.16 Hz, 1H), 2 30-2.40 (m, 2H), 2.44-2.49 (m, 1H), 2.54 (t, J = 7.55 Hz, 2H), 2.53-2.61 (m , 1H), 2.65 (dd, J = 11.83, 4.28 Hz, 1H), 3.03 (dd, J = 12.09, 6.55 Hz, 2H), 4.96 (br. s, 1H), 4.80 (d, J = 1.76 Hz, 1H), 4.97 (s, 1H), 5.05 (d, J = 1.51 Hz, 1H), 6.66 ( d, J = 8.06 Hz, 1H), 6.75-6.78 (m, 1H).

LC-MS: HRMS (ES +): Calculated for C ₃₁ H ₄₃ NO ₄ ⁺ : 494.3270. Found: 494.3265.

Example B.5

Dodecanoyl chloride (3.12 ml, 13.3 mmol) was added dropwise over 30 minutes at ambient temperature to a mixed mixture of nalmefene hydrochloride (5 g, 1.0 equivalent), toluene (100 ml, 20 ml / g) and triethylamine (4.08 ml, 2.2 equivalents) in an inert atmosphere. Stirring at ambient temperature is continued for 16 hours. Then the reaction mixture was washed with water (400 ml, 20 ml / g). After phase separation, the organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 6.36 g (92%) of compound (5).

NMR:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.08-0.16 (m, 2H), 0.44-0.51 (m, 2H), 0.81-0.89 (m, 4H), 1.15-1.42 (m, 18H ), 1.53 (dt, J = 12.78, 3.30 Hz, 1H), 1.63 (q, J = 7.43 Hz, 2H), 1.96 (td, J = 12.09 , 3.53 Hz, 1H), 2.06 (dt, J = 13.60, 3.15 Hz, 1H), 2.24 (td, J = 12.46, 5.04 Hz, 1H), 2 , 29-2.40 (m, 2H), 2.45-2.49 (m, 1H), 2.53 (t, J = 7.68 Hz, 2H), 2.53-2.60 (m , 1H), 2.65 (dd, J = 11.96, 4.41 Hz, 1H), 3.03 (dd, J = 11.96, 6.67 Hz, 2H), 4.99 (br. s, 1H), 4.80 (d, J = 1.76 Hz, 1H), 4.96 (s, 1H), 5.05 (d, 1H), 6.66 (d, J = 8.06 Hz, 1H), 6.76 (d, J = 8.06 Hz, 1H).

LC-MS: HRMS (ES +): Calculated for C ₃₃ H ₄₇ NO ₄ ⁺ : 522.3583. Found: 522.3590.

C.1 Pharmacokinetic (FC) studies in vivo in dogs (v / m injection): plasma levels of nalmefene

A single intramuscular injection of nalmefene, compound (1) or compound (2) is carried out at a concentration of 20 mg equivalent to nalmefene / ml in sesame oil or migliol to three dogs at a dose of 1 mg equivalent to nalmefene / kg body weight.

As an evaluated comparison option, a composition with quick release (IR) of nalmefene at a concentration of 0.40 mg / ml in saline is used, by intramuscular injection (IM) of a single dose in an amount of 0.02 mg of nalmefene equivalent / kg body weight.

Blood samples were taken within 27 days if a dose of the prodrug composition was administered and within 48 hours after the dose of the composition with rapid release of nalmefene was administered. Blood samples are processed to obtain plasma. Next, these plasma samples are analyzed individually for the presence of nalmefene using the established LC-MS / MS method.

The analysis of the obtained pharmacokinetic data is carried out on the profiles of individual plasma concentrations according to the method of pharmacokinetic analysis without compartmentalization using the validated WinNonlin software (v. 4.0.1a).

Results:

Plasma profiles of nalmefene (ng / ml) after intramuscular (i / m) administration of a dose of compound (1) or IR composition of nalmefene itself are shown in FIG.

Plasma concentrations of nalmefene were determined up to 20 days after the dose of the compound (2) and within 27 days after the dose of the compound (1).

C.2. In vivo Dog Pharmacokinetic (FC) Studies (Oral Administration): Plasma Nalmefene Levels

Doses of 10 mg / kg or 20 mg / kg body weight of a compound of formula (I) or nalmefene itself in a solution of 20% HP-β-CD (hydroxypropyl-β-cyclodextrins) were administered orally to dogs.

Blood samples were taken within 192 hours after oral administration. Blood samples were processed to obtain plasma. Plasma samples were analyzed separately for the presence of nalmefene using the established LC-MS / MS method.

The plasma concentration of nalmefene was determined within 192 hours after the dose of the compound (2) was administered.

Description of drawings

Figure 1 shows the plasma concentration of nalmefene (ng / ml), determined by measurement within a 28-day period after the / m administration of a composition containing nalmefene and compound (1).

Claims (14)

1. The compound of formula (I)

where R ¹ denotes C _6-16 alkyl or C _8-12 alkylamino;
or a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, where R ¹ denotes C ₇ alkyl, C ₉ alkyl, C ₁₁ alkyl or C ₁₅ alkyl. 3. The compound according to claim 1, where R ¹ denotes C ₁₀ alkylamino. 4. The compound according to claim 1, which represents
or

or

or

or

5. The compound according to claim 1, which represents

6. A pharmaceutical composition having an opioid receptor antagonist action, comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any one of claims 1 to 5. 7. A method of obtaining a pharmaceutical composition according to claim 6, characterized in that the therapeutically active amount of a compound according to any one of claims 1 to 5 is thoroughly mixed with a pharmaceutically acceptable carrier. 8. The compound according to any one of claims 1 to 5, intended for the treatment of disorders associated with substance abuse and disorders control impulses. 9. The compound of claim 8, wherein said compound is administered intramuscularly or subcutaneously. 10. The compound according to any one of claims 1 to 5, intended for the preparation of a medicament for the treatment of substance abuse disorders, such as alcoholism and alcohol dependence, and impulse control disorders, such as pathological addiction to games and shopping. 11. The compound of claim 10, intended for obtaining a medicinal product, where the specified drug is administered intramuscularly or subcutaneously. 12. The compound according to claim 11, intended for obtaining a medicinal product, where the specified drug is a drug with a slow release. 13. A method of obtaining a compound of formula (Ia), which is a compound of formula (I) according to claim 1, in which R ¹ denotes C _6-16 alkyl, including esterification, which can be carried out by known methods by reacting nalmefene (II) hydrochloride with an acyl halide of the formula (III) in the presence of a base, with the selection of the acid released during the reaction

14. A method of obtaining a compound of formula (Ib), which is a compound of formula (I), where R ¹ is C _8-12 alkylamino, comprising reacting nalmefene (II) hydrochloride with an isocyanate of formula (IV)

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